Comparison of the effects of hydrophobicity, amphiphilicity, and α‐helicity on the activities of antimicrobial peptides

Pathak, Naveen; Salas-Auvert, Rodolfo; Ruche, Gaël; Janna, Marie-hélène; McCarthy, David; Harrison, Roger G.

doi:10.1002/prot.340220210

Cited by 88 publications

(69 citation statements)

References 15 publications

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“…From observation of the major conformation, it is evident that under these conditions, GS14K4 partially exists in a ␤-sheet-like secondary structure as evidenced by the and torsion angles that fall within the range for a antiparallel sheet. There is also evidence from the ensemble for proximity of cross-strand atoms, including the ␣-protons of residues 4 and 9 and residues 2 and 11, and for the expected cross-strand hydrogen bonds between Leu 3 and Val 10 , Lys 5 and Leu 8 , and Val 1 and Leu 12 , thus further indicating that this diastereomer exists in a ␤-sheet-like conformation. In addition, the two type IIЈ ␤-turns that are present in GS14 are also observed in a similar conformation in GS14K4 and therefore allow the two strands to be brought into proximity to form the antiparallel sheet.…”

Section: Nmr Spectroscopy and Structure Determination Of Gs14k4mentioning

confidence: 92%

Development of the Structural Basis for Antimicrobial and Hemolytic Activities of Peptides Based on Gramicidin S and Design of Novel Analogs Using NMR Spectroscopy

McInnes¹,

Kondejewski

Hodges

et al. 2000

Journal of Biological Chemistry

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The structures of 14-residue head-to-tail cyclic gramicidin S peptides have been investigated to develop the structural rationale for their antimicrobial and hemolytic profiles. The basis for these studies is GS14 (cyclo-(VKLKVdYPLKVKLdYP)), designed as an extension of the naturally occurring antimicrobial peptide. The structure of GS14 has been determined using NMR methods and was found to exist in a highly amphipathic antiparallel ␤-sheet conformation. Systematic enantiomeric substitutions within the framework of the GS14 peptide were found to decrease the amphipathicity of this molecule. These results indicated that there was a direct correlation between the high amphipathic character and potent hemolytic activity in the diastereomers, whereas an inverse correlation existed between amphipathicity and antimicrobial function. To define the structural consequences of changing the amphipathic nature of GS14 analogs to maximize antimicrobial activity and to minimize hemolysis, NMR structures were determined in water and the membranemimetic solvent trifluoroethanol. The structures show that these attributes are the result of induction of the ␤-sheet character in a membrane environment and the positioning of charged side chains on the hydrophobic face of the cyclic framework, thus decreasing the amphipathicity and directed hydrophobicity of these molecules. Implications for the design of more effective antimicrobials are discussed.

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Section: Nmr Spectroscopy and Structure Determination Of Gs14k4mentioning

confidence: 92%

Development of the Structural Basis for Antimicrobial and Hemolytic Activities of Peptides Based on Gramicidin S and Design of Novel Analogs Using NMR Spectroscopy

McInnes¹,

Kondejewski

Hodges

et al. 2000

Journal of Biological Chemistry

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“…Several studies have shown that on the angle of helix content the mean hydrophobic moment is a more important factor affecting antimicrobial activity than hydrophobicity (Pathak et al, 1995;Fernandez-Vidal et al, 2007). The measurements of the interfacial partitioning of a family of 17-residue amidated-acetylated peptides into both neutral and anionic lipid vesicles showed that peptide helicity in water and interface increased linearly with hydrophobic moment, as did the favorable peptide partitioning free energy.…”

Section: Amphipathicity and Hydrophobic Momentmentioning

confidence: 99%

Alpha-helical cationic antimicrobial peptides: relationships of structure and function

2010

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Antimicrobial peptides (AMPs), with their extraordinary properties, such as broad-spectrum activity, rapid action and difficult development of resistance, have become promising molecules as new antibiotics. Despite their various mechanisms of action, the interaction of AMPs with the bacterial cell membrane is the key step for their mode of action. Moreover, it is generally accepted that the membrane is the primary target of most AMPs, and the interaction between AMPs and eukaryotic cell membranes (causing toxicity to host cells) limits their clinical application. Therefore, researchers are engaged in reforming or de novo designing AMPs as a 'singleedged sword' that contains high antimicrobial activity yet low cytotoxicity against eukaryotic cells. To improve the antimicrobial activity of AMPs, the relationship between the structure and function of AMPs has been rigorously pursued. In this review, we focus on the current knowledge of α-helical cationic antimicrobial peptides, one of the most common types of AMPs in nature.

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“…An increase in the antimicrobial activity of a linear ␣-helical antimicrobial peptide has been shown in several cases to correlate closely with an increase in ␣-helical secondary structure (19,20). To examine the contribution of ␣-helical secondary structure to the antimicrobial activity of buforin II, CD spectra of buforin II and its analogs were obtained.…”

Section: Relationship Between the ␣-Helical Content Of Truncated Bufomentioning

confidence: 99%

Structure–activity analysis of buforin II, a histone H2A-derived antimicrobial peptide: The proline hinge is responsible for the cell-penetrating ability of buforin II

Park

Yi²,

Matsuzaki³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

479

385

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Buforin II is a 21-aa potent antimicrobial peptide that forms, in a hydrophobic medium, an amphipathic structure consisting of an N-terminal random coil region (residues 1-4), an extended helical region (residues 5-10), a hinge (residue 11), and a C-terminal regular ␣-helical region (residues 12-21). To elucidate the structural features of buforin II that are required for its potent antimicrobial activity, we synthesized a series of N-and C-terminally truncated or amino acid-substituted synthetic buforin II analogs and examined their antimicrobial activity and mechanism of action. Deletion of the N-terminal random coil region increased the antibacterial activity Ϸ2-fold, but further N-terminal truncation yielded peptide analogs with progressively decreasing activity. Removal of four amino acids from the C-terminal end of buforin II resulted in a complete loss of antimicrobial activity. The substitution of leucine for the proline hinge decreased significantly the antimicrobial activity. Confocal fluorescence microscopic studies showed that buforin II analogs with a proline hinge penetrated the cell membrane without permeabilization and accumulated in the cytoplasm. However, removal of the proline hinge abrogated the ability of the peptide to enter cells, and buforin II analogs without a proline hinge localized on the cell surface, permeabilizing the cell membrane. In addition, the cell-penetrating efficiency of buforin II and its truncated analogs, which depended on the ␣-helical content of the peptides, correlated linearly with their antimicrobial potency. Our results demonstrate clearly that the proline hinge is responsible for the cell-penetrating ability of buforin II, and the cellpenetrating efficiency determines the antimicrobial potency of the peptide.

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Comparison of the effects of hydrophobicity, amphiphilicity, and α‐helicity on the activities of antimicrobial peptides

Cited by 88 publications

References 15 publications

Development of the Structural Basis for Antimicrobial and Hemolytic Activities of Peptides Based on Gramicidin S and Design of Novel Analogs Using NMR Spectroscopy

Development of the Structural Basis for Antimicrobial and Hemolytic Activities of Peptides Based on Gramicidin S and Design of Novel Analogs Using NMR Spectroscopy

Alpha-helical cationic antimicrobial peptides: relationships of structure and function

Structure–activity analysis of buforin II, a histone H2A-derived antimicrobial peptide: The proline hinge is responsible for the cell-penetrating ability of buforin II

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